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The Return of the Cholinergic Hypothesis

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The Return of the Cholinergic Hypothesis The return of the cholinergic hypothesis. R J Wurtman J Clin Invest. 1994;94(2):470-470. https://doi.org/10.1172/JCI117356. Editorial Find the latest version: https://jci.me/117356/pdf The Return of the Cholinergic Hypothesis Editorial Although many types of neurons are damaged or destroyed in Alz- in the frequency with which the surviving neurons were firing, heimer's disease, few seem to fare so badly as the cholinergic cells perhaps an adaptive response to the loss of neurons and the which arise in the basal forebrain, terminate in the hippocampal and impairments in cholinergic neurotransmission that are charac- cerebral cortex, and enable some memory functions (compare with teristic of the disease. (It might also constitute an adaptation to reference 1). Identifying the biochemical processes which underlie the recently demonstrated decrease in choline transport across the selective vulnerability of these cells has been a continuing focus the blood-brain barrier associated with aging, per se [5].) How- of Alzheimer's disease research. A potential candidate is the propen- ever, this acceleration in neuronal firing rates, they propose, sity of these cells to use choline for two purposes: to phosphorylate may be damaging to the cholinergic cells, further diminishing it, ultimately generating a major membrane phospholipid, phosphati- the formation of PC and perhaps accelerating its turnover. They dylcholine (PC), a pathway they share with all other cells; and to suggest that drugs be developed which will restore cholinergic acetylate it to form the neurotransmitter acetylcholine (ACh). Both transmission while decreasing neuronal firing (for example, the of the neuronal enzymes which act on choline, choline kinase and cholinergic agonists discussed above): agents which cause the choline acetyltransferase, have unusually low affinities for this sub- neuron to fire yet more frequently (like GABA antagonists or strate and are thus unsaturated at normal brain choline levels. Thus, glutamate agonists) should be avoided, since flogging the dying they rapidly synthesize more product when substrate levels increase horse may only hasten its death. This suggestion seems reason- (e.g., after administration of compounds that raise plasma choline able, and one can only hope that appropriate agents will soon levels [1]). However, when cholinergic neurons are physiologically become available for testing. active, they selectively shunt available free choline to the ACh Should Alzheimer's disease patients also receive supplemental pathway, increasing the turnover of membrane PC and slowing its choline, as such or in the form of choline-rich molecules like PC synthesis, and, if unchecked by giving supplemental choline, actually or cytidyldiphosphocholine? Such supplements might cause less decrease the amounts of membrane phospholipids per cell (1). This of an increment in brain choline levels among old Alzheimer's process, a kind of "autocannibalism" is perhaps analogous to the disease patients than in young subjects (5). However, they have bone demineralization which occurs with prolonged vitamin D defi- in fact been shown to raise cerebrospinal fluid choline concentra- ciency. tions in such patients (6). Even if they enhanced ACh release The discovery that providing choline could promote ACh release and/or protected membrane PC from autocannibalism, they still in model systems (1) generated hope that Alzheimer's disease pa- couldn't correct the deficits in brain levels of the closely related tients might benefit from supplemental choline sources, much as amine ethanolamine, nor of the phospholipid phosphatidylethano- those with Parkinson's disease show clinical improvement when lamine (3). However, there is probably little harm (a judgment treated with dopamine's precursor, L-dopa. However, clinical tests which must first be confirmed by suitable toxicologic testing) in of such sources demonstrated only occasional improvement, and providing the choline at a dose requirement to the amount that drugs that increased brain ACh levels (by blocking acetylcholinester- many Americans miss when they give up eggs because of choles- ase) rarely caused dramatic responses. The widespread extracranial terol content. A stronger argument can be adduced for supplying distribution of ACh receptors and the continuing unavailability of choline to patients to be treated chronically with drugs like the selective agonists for the brain-specific ml receptor (which, when cholinesterase inhibitors, which further decrease the free choline activated, improves memory and suppresses formation of the amy- available to cholinergic terminals. The demonstration by Slotkin loid-forming peptide, A-beta, in model systems [2]) precluded ade- et al. (4) of yet another abnormality of cholinergic neurons in quate tests of the hypothesis that drugs which restored cholinergic Alzheimer's disease should stimulate additional studies on the brain function would bestow clinical improvement on Alzheimer's unique biochemical properties of the cells. disease patients. So the "cholinergic hypothesis" of Alzheimer's J. Wurtman disease lost its place in the research line to therapeutic Richard strategies and Sciences based on proteins like APP (the amyloid precursor tau, Department of Brain Cognitive protein), of and the apolipoprotein alleles. Brain levels of choline and of its Massachusetts Institute Technology principal reservoir, PC, were later shown to be reduced in Alzhei- mer's disease, and those of PC's breakdown product glycerophos- References phocholine increased (3). However, these discoveries failed to en- gender new strategies, or drugs, to test in treating the disease. 1. Wurtman, R. J. 1992. Choline metabolism as a basis for the selective Now Slotkin and his colleagues (4) present evi- vulnerability of cholinergic neurons. Trends Neurosci. 15:117- 121. compelling 2. Nitsch, R., B. Slack, R. J. Wurtman, and J. Growdon. 1992. Release of dence that another macromolecule localized to cholinergic neu- Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic rons, the high-affinity carrier that transports extracellular cho- acetylcholine receptors. Science (Wash. DC). 258:304-307. line into cholinergic nerve terminals, also is abnormal in Alzhei- 3. Nitsch, R., J. K. Blusztajn, A. Pittas, B. E. Slack, J. H. Growdon, and R. J. Wurtman. 1992. Evidence for a membrane defect in Alzheimer's disease brain. mer's disease. But the disturbance is opposite to what might Proc. Natl. Acad. Sci. USA. 89:1671-1675. have been expected in a disease that reduces the number of 4. Slotkin, T. A., C. B. Nemeroff, G. Bissette, and F. J. Seidler. 1994. Overex- terminals: transport activity is too high, not too low. They pro- pression of the high affinity choline transporter in cortical regions affected by studies. J. Clin. Invest. 94:696- an Alzheimer's disease. Evidence from rapid autopsy pose that this change resulted, premortem, from acceleration 702. 5. Cohen, B. M., A. Stoll, P. Renshaw, E. DeMicheli, and R. J. Wurtman. 1994. Differences in choline uptake in brain measured in vivo by proton MRS in young and elderly adults. Society for Magnetic Resonance, Abstract. J. Clin. Invest. 6. Growdon, J. H., and M. Logue. 1982. Choline, HVA, and 5-HIAA levels in ©) The American Society for Clinical Investigation, Inc. cerebrospinal fluid of patients with Alzheimer's disease. In Alzheimer's Disease: A 0021-9738/94/08/0470/01 $2.00 Report of Progress (Aging, Volume 19). S. Corkin, K. L. Davis, J. H. Growdon, E. Volume 94, August 1994, 470 Usdin, and R. J. Wurtman, editors. Raven Press, New York. 35-43. 470 R. J. Wurtman.
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